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Outstanding areas of medical research at the University of Alberta include diabetes, obesity, virology, heart disease, motor control and rehabilitation, protein structure and function, and transplantation.

Dennis Vance

Ph.D, University of Pittsburgh

Distinguished University Professor

We investigate the regulation of phosphatidylcholine (PC) biosynthesis in mammalian cells and the function of PC synthesis in liver failure, obesity, and diabetes.

All mammalian cells make PC via the CDP-choline pathway. In addition, the liver makes PC via the methylation of phosphatidylethanolamine (PE) catalyzed by PE methyltransferase (PEMT). We disrupted in mice the gene (Pemt) that encodes PEMT (Walkey et al. 1997). Pemt -/- mice showed no obvious phenotype when maintained on a diet supplemented with choline. However, when fed a choline-deficient diet for 3 days, severe liver failure occurred (Walkey et al. 1998). We concluded that PEMT survived in evolution as a liver specific enzyme to provide choline and PC when the dietary source was insufficient. We have used this and another mouse model to demonstrate that choline is an essential nutrient and that the molar ratio of PC to PE is a key regulator of membrane integrity in mouse liver (Li et al. 2005, 2006). We also demonstrated that livers from male Pemt -/- mice have a defect in the secretion of apo B100-containing very low density lipoproteins (Noga et al. 2002). Consistent with these studies, we have shown that a lack of PEMT will greatly decrease the development of atherosclerosis and lipotoxic cardiac dysfunction in mice (Zhao et al. 2009; Cole et al., Circ. Res. 2011). Pemt -/- mice have a striking protection against diet induced obesity and insulin resistance (Jacobs et al., 2010; Wu et al., 2013; van der Veen et al., 2014). We are now deeply involved in determination of the mechanism by which the lack of PEMT results in a lean, insulin sensitive phenotype. Secondly, we are pursuing ideas to find an inhibitor of PEMT that might be a therapy for obesity and type 2 diabetes.

We also investigated the fate of PC on HDL and LDL when taken up by the liver in mice. In contrast to cholesteryl esters, LDL-PC is not degraded in the lysosomes. Unexpectedly, approximately 50% of LDL-PC is converted to triacylglycerol via reactions catalyzed by phospholipase C and DGAT2 (diacylglycerol acyltransferase 2) (Minahk et al. 2008). The fate of HDL-PC in liver is very similar to the PC derived from LDL (Robichaud et al. 2008, 2009). We have now shown that as much PC is delivered to the liver from lipoproteins as made de novo in liver (van der Veen et al., 2012) and much of this PC is converted to triacylglycerol. The role that PC plays in the formation of fatty liver (steatosis) remains to be investigated. Recent studies have shown that the hepatic branch of the vagus nerve is required for the development of steatosis/steatohepatitis in Pemt -/- mice fed a high fat diet Gao et al., 2015).